2-amino-4-phenyl-2-imidazolines

ABSTRACT

The novel compounds of this invention are of the imidazoline class of heterocycles having substituents in the 2 and 4 imidazoline ring positions and optionally in the 3-position. Substituents in the 2-position include amino, hydroxyamino, alkylamino, benzylamino, halobenzylamino, dihalo benzylamino, allylamino, cycloalkylamino, hydrazino, and alkylidenehydrazino. Optional 3-position subsitutents are alkyl and benzyl. The substituent in the 4-position is comprised of phenyl or R-phenyl in which the R-substituent is selected from halogen, alkyl, benxyloxy, alkoxy, dialkoxy, 3-hydroxy, 3,4-dihydroxy, trifluoromethyl, phenyl, halophenyl, or alkylphenyl. The novel imidazolines have antihypertensive and neuronal blocking properties. They are prepared by cyclization of appropriately substituted 1-phenylethylenediamines with cyanogen bromide or by displacement of a methylmercapto grouping from an appropriately substituted 2-methylthioimidazoline. Representative embodiments of this invention are 2-amino-4-(4-chlorophenyl)-2-imidazoline and 2-amino-4-(3,4-dichlorophenyl)-2-imidazoline.

United States Patent 1 Matier et al.

. [111 3, 21,244 [451 ima e, r974 Z-AMINO-4-PHENYL-2-IMIDAZOLINES [75]Inventors: William LesleyMatier; William Timmey,.Evansville, both ofInd.

[73] Assignee: Mead Johnson & Company,

Evansville, Ind.

[22] Filed: July 3, 1972 [21] Appl. No.: 268,380

Related U.S. Application Data [63] Continuation-impart of Ser. No;172,321, Jan. 16,

197i, abandoned.

[52] US. Cl 260/309.6, 260/240 G, 260/309.7,

260/570.5 P, 260/465 E, 424/273 [51] Int. Cl C07d 49/34 [58] Field ofSearch 260/309.6, 309.7, 240 G [56] References Cited OTHER PUBLICATIONSC A. 61: 652F (196 4) Wollweber et al.

Primary Examiner-l-lenry R. Jiles Assistant Examiner--S. D. WintersAttorney, Agent, or Firm-Robert E. Carnahan; Robert H. Uloth 57]ABSTRACT The novel compounds of this invention are of the imidazolineclass of heterocycles having substituents in the 2 and 4 imidazolinering positions and optionally in the 3-position. Substituents in the2-position include amino, hydroxyamino, alkylamino, benzylamino,halobenzylamino, dihalo benzylamino, allylamino, cycloalkylamino,hydrazino, and alkylidenehydrazino. Optional 3-position subsitutents arealkyl and ben zyl. The substituent in the 4-position is comprised ofphenyl or R-phenyl in which the R-substituent is selected from halogen,alkyl, benxyloxy, alkoxy, dialkoxy, 3-hydroxy, 3,4-dihydroxy,trifluoromethyl, phenyl, halophenyl, or alkylphenyl. The novelimidazolines have antihypertensive and neuronal blocking properties.They are prepared by cyclization of appropriately substitutedl-phenylethylenediamines with cyanogen bromide or by displacement of amethylmercapto grouping from an appropriately substituted 2-methylthioimidazoline. Representative embodiments of this invention are2-amino-4-(4-chlorophenyl)-2- imidazoline and2-amino-4-(3,4-dichlorophenyl)-2- imidazoline.

29 Claims, No Drawings 1 2-AMTNU4 FfiENYL-i-TMIDAZGCINES CROSS-REFERENCETO RELATED APPLICATTON This application is a continuation-in-part ofcopending application Ser. No. 172,321, filed Aug. 16, 1971, nowabandoned.

BACKGROUND OF THE INVENTION The present invention is concerned withsubstituted imidazolines and acid addition salts thereof. This inventionrelates to novel imidazolines displaying a useful range of biologicalproperties. They are, specifically, neuronal blocking and/orantihypertensive agents.

Neuronal blocking agents are capable of producing a pharmacologicaleffect similar in many respects to a sympathectomy. Such agents are ofinterest in experimental biology,'comparative pharmacology, and in thetreatment of hypertension. For example, guanethidine,

SUMMARY OF THE INVENTION This invention relates generally to a series ofnovel imidazolines-More particularly, it relates to imidazolines havingsubstituents in the 2, 4, and optionally in the 3 positions of theimidazoline ring and to the nontoxic pharmaceutically acceptable acidaddition salts which are independently selected from halogen andthereof. The imidazolines of this invention possess valuablepharmacological properties, including neuronal blocking activity, whichrender them useful as antihypertensive agents. This invention is furtherconcerned with a therapeutic process for producing a neuronal blockingeffect in mammals comprising the administration of the imidazolines ofthe present inven-.

tion thereto.

The novel imidazolines of the present invention are.

I comprised of imidazolines which have substituents in the 2,3, and 4positions represented by A, B, and Y When Y is the phenyl radical, A isselected from a group consisting of benzylamino, halobenzylamino, e.g.,4-chlorobenzylamino, 2-chlorobenzylamino, 2,6 dichlorobenzylarnino,3,4-dichlorobenzylamino; and 3-dimethylaminopropylamino.

lower alkyl.

Radical A in the 2 position when Y is' R-phenyl represents a member ofthe group consisting of amino, hydroxyamino, lower alkylamino,benzylamino,-halobenzylamino, dihalobenzylamino, allylamino,cycloalkylamino from three to six carbon atoms inclusive, e.g.,

cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino;hydrazino, halobenzylidenehydrazino, e. g., 4-chlorobenzylidenehydrazino, 2- chlorobenz'yliden'ehydrazino;dihalobenzylidenehydrazino, e.g., 3,4-dichlorobenzylidenehydrazino, 2,6-dichlorobenzylidenehydrazino; and alkylidenehydrazino.

It is to be understood that bythe term lower alkyl and lower alkoxy asused herein, it is meant that the carbon chains which comprise thesegroups include both straight-and branchedchain carbon radicals of one tofour carbon atoms inclusive. Exemplary of these carbon chain radicalsare methyl, ethyl, propyl, isopropyl, l-butyl, l-methylpropyl,2-methylpropyl, and'tert.- butyl.

By the term independently selected" as used herein it is meant that thehalogen or lower alkyl substituents may or may not be identical whentheR group in the phenyl radical consists of halogen and lower alkyl.

By the term alkylidene, as utilized herein, it is intended to refer tocarbon chains of from two to six carbon atoms inclusive which aredouble-bonded through a singlecarbon atom. thereof to the hydrazinegroup. They are derived from alkyl aldehydes such as acetaldehyde,prbpionaldehyde,butyraldehyde, isobutyraldehyde, hexaldehyde and thelike, or. alkanones such as acetone, methylethylketone, diethylketone,2- heptanone and the like, Exemplary of suitable-alkylidene radicals areillustratively represented by the formu es omi; amok oi; 1635;55,omortorig ciitofibiofi It is to be understood that the term non-toxicpharmaceutically acceptable acid addition salts used herein denotes acombination of the imidazoline bases which depict various positionaltautomers of 2-amino- 4-(4-chlorophenyl)imidazoline and2-amino-3-benzyl- 4-(4-chlorophenyl) imidazoline bases.

Without being bound by any theory, we believe that protonatedimidazolines, as is the case with the acid addition salts, are bestrepresented by a delocalized double bond rather than fixed double bondsas shown in the above tautomeric forms. Illustrating a delocalizeddouble bond is structure 6 which represents a salt of 2-amino-4-(4-chlorophenyl)-2-imidazoline in which X symbolizes an anion.

Evidence that double bonds in the subject imidazolines are delocalizedrather than fixed is provided by infrared spectra which clearly showstrong NH absorption in the free amino region (3,lOO-3,400 Cmf) ratherthan in the ammonium region and strong C=N absorption at 1,685 Cm. whichis characteristic of a disubstituted guanidinium. g The novelimidazolines which are the subject of the present invention can bedepicted according to theFormulas l and ll wherein the symbol B has themeaning defined above. Dotted lines which'extend from ring position 2represent a delocalized bond which is intended to represent theinterchangeable tautomeric forms of the novel imidazolines illustratedby structures 1-5.

R1 N-H l Q 4 I m "A T: III"" A Formula 1 Formula II in Formula I, Rcanbe hydrogen in which case the symbol A signifies a member of thegroup consisting of benzylamino, halobenzylaminodimethylaminopropylamino.

ln Formula I, R can also signify a halogen, lower alkyl, benzyloxy,lower alkoxy, lower dialkoxy, -T-hymXy, 3,4-dihyd'roxy, trifiuoromethyl,phenyl, 4-halophcnyl, and 4-(lower alkyl)phcnyl. Whenever R is asdescribed above, but excluding hydrogen, A signifies a member of thegroup consisting of amino, hydroxyamino, lower alkylamino, benzylarnino,halobenzylamino, dihalob'enzylamino, allylamino, cycloalkylamino,hydrazino, halobenzylidenehydrazino, dihalobenzylidenehydrazino, andalkylidenehydrazino. In Formula II, R signifies halogen or lower alkyland R" and R signify independently selected halogen or lower alkyl; andA is as above when R excludes hydrogen. By halo and halogen it isintended to include all four. halogens.

It will be readily apparent to those skilled in the art that compoundsof the present invention exist as stereoisomers inasmuch as position 4"of the imidazoline ring contains an asymmetriccarbon atom and it is tobe understood that all stereoisomeric forms of the substances ofFormulas l and ll are included within the scope of the presentinvention. Racemic modifications of the imidazolines can be resolvedinto optical antipodes according to procedures known to the art such as,by reaction with optically active acids to provide diastereoisomericsalts. Separation of these salts according to physico-chemicalproperties and liberation of the optically active bases from the salts.

An alternate and preferred method providing the optical antipodes of thesubstances of this invention is to employ optically purel-phenylethylenediamines, These amines can be cyclized to the opticallyactive imidazolines of the present invention according to methodshereinafter described.

,A preferred process for preparing novel imidazolines of the presentinvention wherein the A radical is limited to amino is represented bythe following reaction scheme in which R and B have the same meaninggiven above.

R NH-B NH,

and 3- Formula III a g r e N '-----N1r: R B

Formula IV The cyclization proceeds when the -1- phenylethylenediamineand cyanogen bromide are contacted and mixed in an inert organic solventas a reaction medium. Benzene is a preferred solvent for the cyelizationbut other solvents may also be employed, such as, ether, toluene,acetonitrile, chloroform, and the like. Preferably, the reaction isconducted at a temperature of about 25C. and is complete in from about0.5 hr. to 16 hr. Reaction temperatures'appreciably below roomtemperature can be used but their use may extend the reaction time.Similarly, reaction temperatures higher than 25C. can be employed with aconcomitant decrease in reaction time.

After the reaction is complete, the product is obtained by conventionalmethods, for example by filtration and crystallization from a suitablesolvent. such as alkanols, water, alkanones, and ethcrs.

Displacement of the Z-methylthio functionally of 2-methylthioimidazolines according to the following reaction schemeprovides imidazolines wherein the symbols B, Y, and A are as definedabove.

Formula. V Formula VI This is a particularly preferred methodfor theprepara tion of the novel imidazolines wherein A is limited to the groupconsisting of hydroxyamino, lower alkylamino, benzylamino,halobenzylamino, 2-(3- dimethylaminopropylamino), and hydrazino.

The Z-methylthioimidazoline intermediates are obtained by cyclizingl-phenylethylenediamines with carbon disulfide according to the methoddescribed in US. Pat. No. 3,274,209 to Z-thioirriidazolines which arethen S-methylated by treatment with methyl iodide. Illustrative of thecyclization and subsequent S- methylation and displacement reactionsisthe following transformation of l-(2-chlorophenyl)ethylenediamine into4-(2-chlor'ophenylj-Z-hydrazino-Z- imidazoline hydriodide as depictedbelow in structures 7-10.

lCHaI methods in themselves wcll'known; refer to Wagner and 200k,Synthetic Organic Chemistry (Wiley) pages A preferred method comprisescyanoammonolysis of the corresponding substituted benzaldehyde accordingto the Strecker synthesis to provide oz-aminophenylacetonitriles ora-benzylaminophenylacetonitriles which are then reduced by catalytic orchemical means tothe l-phenylethylenediamines;

Some of the substituted benzaldehydes which may be used are:

4-chlorobenzaldehyde,

2-chlorobenzaldehyde,

4-bromobenzaldehyde,

2,4-dichlorobenzaldehyde,

2,-dichlorobenzaldehyde,

3,4-dichlorobenzaldehyde, 2,4-dibromobenzaldehyde,

4-methylbenzaldehyde,

4-ethylbenzaldehyde,

4-propylbenzaldehyde,

4-isopropylbenzaldehyde,

'4-butylbenzaldehyde,

4-tert.-butylbenzaldehyde,

4-fluorobenzaldehyde,

4-trifluoromethylbenzaldehyde,

3-trifluoromethylbenzaldehyde, 4-methoxybenzaldehyde,

-3-methoxybenzaldehyde,

3-benzyloxybenzaldehyde,

3,4-dimethoxybenzaldehyde,

3,4-dibenzyloxybenzaldehyde, and the like.

Reduction of a-aminonitriles such as a-amino-2,6-dichlorophenylacetonitrile is carried out with diborane or lithiumaluminum hydride in an inert solvent, e.g., tetrahydrofuran or ether.With a-benzylaminophenylacetonitriles, the preferred route is firstreduction with lithium aluminum hydride in ether at 0C. to a,B-benzylaminophenethylamine which is then debenzylated catalyticallyemploying palladium on carbon catalyst, or cyclized with cyanogenbromide as described above.

The imidazolines of the present invention have valuable neuronalblocking properties and thus are particularly useful in experimental andcomparative pharmacolog y and in treating conditions in mammalsresponsive to administration of such agents. They are of particularimportance in the treatment of hypertensive.

, mammals, substantially reducing blood pressure when orally orparenterally administered thereto.

Neuronal blocking effects can be demonstrated in standard in vitro andin vivo pharmacological tests such as, for example, the rabbit jejunumtest of B. Finkelman, J. PhysioL, 70, 145 l930). In this test,electrodes are threaded to mesenteric periarterial nerves of the rabbitjejunum andthe preparation is mounted in Tyrodes solution aerated with95 percent oxygen and 5 percent carbon dioxide. Spontaneous motility ismeasured employing a base line tension of 1 gram and a 2 millisecondelectrical pulse is then delivered to the electrodes at a frequency of50 per second for 10 seconds. The lowest voltage is selected for eachtissue which produces greater than percent inhibition of spontaneousmotility. Antagonism of the electrical nerve stimulation expressed aspercent inhibition is determined by comparison of pre-drug controlresponse with those obtained at 5, 10, and minute intervals after drugaddition. A blocking concentration (BC- is known compound of analogousstructure. The latter exhibits only 0.03 times the activityol'guanethidine in azolines of the present invention are reported inTable I. Activity is expressed as a multiple of the neuronal blockingactivity of guanethidine which is taken as unity.

TABLE I.

NEURONAL BLOCKING ACTIVITY RELATIVE TO GUANETHIDINE (=1) Example"Chemical Name Rel. Act.

1 Z-amino-4-(2-chlorophcnylJ'Z- 4.3

imidazoline hydrobromide l 2-amino-4-(Z-chIorophenyD-Z- 3.0

imidazoline hydrobromidc levorotatory I l 2-amino-4-(2chlorophenyl)2-3.8

imidazoline hydrobromide dextrorotatory 2 benzylarnino-4- 2(Z-chlorophenyU-Z- imidazoline hydriodide 34-(2-chlorophcnyl)-2-hydrazino-2- 10.0

imidazoline hydriodide 4 4-( 2-chlorophenyl)-2hydroxyamino-2- 1.5

imidazoline hydrochloride 5 v 4-(Z-chlorophenyl)-2-isopropylidencl0.0

hydrazino-Q-imidazoline hydriodide s 2-amino-4-(4-chlorophenyl)-2- 2.0

imidazoline hydrobromide 7 2-amino-'4-(4-bromophenyl)-2 0.6

imidazoline hydrobromide t1 2-amino-4-t 2.4-dichlorophenyU-2- 3.0

imidazoline hydrobromide 9 2-amino-4-(2.6-dichlorophenylJ-2- 3.0

imidazoline hydrobromide l0 2-amino 4-(3.4-dichlorophenyl)-2- 1.5

imidazoline hydrobromide l l 2-amino-4-( m-tolyl)-2-imidazoline- 0.43

hydrobromide l2 2-amino-4-(p-tolyl)-2-imidazoline 3.0

hydrohromide l3 2-umino-4-( 4-methoxyphenyl )-2- 1.0

imidazoline hydrobromidc l4 Z-amino-4-(4-benzyloxyphenyl)-2' 0.75

imidazoline hydrobromide l5 2-zimino-4-(4-biphenyl)-2-in1idazoline 0.6

hydrobromide 16 Z-amino-l-benzyl-5'(2-chlorophenyl)- 0.15

Z-imidazoline hydrobromide 27 2-amino-4-(3-chlorophenyl)-2 0.03

imidazoline hydrobromide 56 2-amino-4-l3.4-dimethoxyphenyll'2 0.003

imidazoline hydrobromide 58 2-nmino-4-t3.4-dihydroxyphenyU-2- ().03

imidazoline hydrobromide 59 2-henzylamino-4-phenyl-2imidazoline 0.15

fumzirute 60 2-(4chlorobenzylamino)-4-phenyl-2- 0.3

imidazolinefumurate 61 Z-t3-dimcthylaminopropylamino)-4- 0.003

phcnyl-2-imidazoline dihydrochloridc 622-(2.(a-dichlorobenzylidenehydrazinol 0.03

4-(2-chlorophcnyl)-2-imidazoline hydriodide 634-(d-chlorophenyl)-2-(methylamino)-2- 0.075

imidazoline hemimucate 64 4(4chlorophenyl)-2-hydrazino-2- 10.0

imidazoline hydrochloride "Preparation infril.

The neuronal blocking activity of the subject imidaz- 65 this test.

Compounds of the instantinvcntion which are particularly preferred fortheir strong neuronal blocking action are2-amino-4-R-phenyl-Z-imidazolines wherein R is as defined above and thecorresponding Z-hydrazino and 2-alkylidenehydrazino imidazolines. Therecan be mentioned as particularly valuable embodiments of the presentinvention, the following compounds:

2-amino-4-(2-chlorophenyl)-2-imidazoline and its hydrobromide;levorotatory 2-amino-4(2-chlorophenyl)-2- imidazoline and itshydrobromide; dextrorotatory 2-amino-4-(2-ch1orophenyl)-2- imidazolineand its hydrobromide; 2-amino-4-(4-chlorophenyl)-2-imidazoline and itshydrobromide; 2-amino4-(4-bromophenyl)-2-imidazoline and itshydrobromide;

2-amino-4-(para-tolyl)-2-imidazoline and its hydrobromide;2-amino-4-(2.4-dichlorophenyl)-2-imidazoline its hydrobromide;2-amino-4-(4-biphenyl)-2-imidazoline and its hydrobromide; 2-amino-4-(2,6-dichlorophenyl)2 imidazoline and its hydrobromide; 2-amino-4-(3,4-dichlorophenyl )-2-imidazoline and its hydrobromide;2-amino-4-(4-methoxyphenyl)-2-imidazoline and its hydrobromide;

4-( 2-chlorophenyl )-2-hydrazino-2-imidazoline its hydriodide;4-(2-chlorophenyl)-2-isopropylidenehydraZino-Z- imidazoline and itshydriodide; 4-(2-chlorophenyl)-2-hydroxyamino-2-imidazoline and itshydrochloride.

The antihypertensive effects of the imidazolines of the presentinvention can be demonstrated in hypertensive rats. Hypertension isproduced in Sprague Dawley male rats, weighing -100 grams each, bysubcutaneous administration of desoxycorticosterone acetate (DOCA) at adose of 10 mg./rat/day for five days each week for three weeks. Onepercent saline is provided ad libitum for the three-week period. At theend of the treatment period tap water is substituted for the l percentsaline. Systolic blood pressures are determined by the tail cuff method,utilizing capacitance transducers for the detection of pressure, ananeroid manometer for measuring pressure, and an oscilloscope forvisualizing the disappearance and/or appearance of the pressure pulse.Groups of five rats each having a systolic blood pressure of mmHg orgreater are selected and the test compound administered at a dose of 5mg.- /kg. subcutaneously in sterile water at a constant volume of 2.5ml./kg. One group serves as a control and receives the water vehicle,while another receives an antihypertensive reference agent such asguanethidine sulfate, (subcutaneous dose of 20 mg./kg.) The test groupsreceived the test agent or vehicle at O and 24 hr. Blood pressure andheart rate measurements are made at 0 time (immediately prior to thefirst dose), 4.24 (immediately prior to the second dose) 28, and 48 hr.

and

and

Data provided by this test includes absolute systolic blood pressures inmmHg and heart rates in beats per 9 minute, changes in pressure and rateversus the respective time values, and percent changes in pressure andrate. By plotting the percent decrease in blood'pressure as a functionof time and determining the area under the resulting curve, an overallindex of antihypertensive activity can be obtained. I

The test agent is rated very active if either the actual blood pressureor percent decrease in pressure differed significantly (as measured byconventional statistical analysis) at all post treatment intervals. Theyare rated active" when there is a significant difference in either theactual pressures or percent decreases in pressure at either (a) 4 and 28hr. or (b) 24 and 48 hr. posttreatment. Test agents showing at least onerandom significant difference are rated slightly active and thoseexhibiting no significant difference are classified as inactive." On thebasis of area under the percent decrease in pressure-time curve,compounds Were considered very active when the area exceeded 600 units,ac-

100 to 300 units, and inactive below I units.

In Table. II, results obtained with representative imidazolines of thepresent invention are reported-The last column is a composite rating forthe test agent calculated from the first three columns by (a)arbitrarily assigningnumericvalues of (very active), 2 (active), 1(slightly active), and 0 (inactive) for each rating, (b) summing theassigned numeric values for actual blood pressure, percent decrease inblood pressure, and area under the time curve; and (c) applying thefollowing ratings to those totals: very active, 89 (9 equals maximumscore); active (4-7); slightly active (2-3); and inactive (0-1 It is tobe understood that these ratings are derived from a one dose levelmg./kg. body weight) assay and consequently are considered onlysemi-quantitative and that increasing the dosage, according to acceptedpharmaceutical practice, of test agents classified. herein as inactiveor slightly active" could produce an increased antihypertensive eftivebetween 300 and 600 units, slightly active from feet.

' TABLE II ANTIHYPERTENSIVE ACTIVITY RATING" Activity Based On AreaUnder Actual RP. 71 Deer-ease '71 Decrease Composite Example" ChemicalName Decrease in B.P. Time Curve Total Rating l2-amino-4-(ZchIorophenyU-Z- I I SA I I imidazoline hydrobromideIevorotatory (I88 i I32) l 2-amino-4(2-chlorophcnyl)-2- SA A A a 5 Aimidazoline hydrobromide dextrorotatory (420 i 23) 22-benzyIamino-4-(2-chlorophcnyl)-2- I SA l l I I imidazoline hydriodide(52 i 45) 3 4-(2-chlorophenyl)-2-hydrazino-2r SA SA A 4 A imidazolinehydriodide (387 1 I) 4 4(2-chlorophenyl)-2-hydroxyamino- SA SA SA 3 SAZ-imidazoline hydrochloride (I67 i 46) 5 4(2-chlorophenyl)-2-isopropylidene- A A A 6 A hydrazino-Limidazolinehydriodide (484 i I23) 6 Z-amino-4-(4-chlorophenyl)-2 SA SA A. 4 A

imidazoline hydrobromide (413 i I) 7 Z-amino-4-(4-bromophenyl)-2- A 6 Aimidazoline hydrobromide 1 (48,4 l I I) 8 Z-am ino-4-(2,4-dichlorophenyl )-2 A (i A imidazoline hydrobromide (508 i 87) 9'l-amino-4-(2,6 dichlorophenyl)-2 SA VA 6 A imidazoline hydrobromide((157 i )2) It) 2-amino-4-(3,4-dichIorophenyU-2- VA VA VA VA.imidazoline hydrobromide 7 (I21 I i 84) I I2-amino-4-(m-toIyl)-2-imidazoline SA A 5 A hydrobromide (3791" I29) I 22-amino-4-( p-tolyl )2-imidazoline A A A o A hydrobromide v (425 I 34) I3 2-amino-4-( 4-methoxyphenyI)-2- SA SA SA 3 SA imidazoline hydrobromide(220 z; 62) I4 2-amino-4-(4-henzyloxyphenylI-2- I I I I O I imidazolinehydrobromide (3) i: 78) I5 2-ani ino-4-( 4-biphenylyl )-2- A A A o Aimidazoline hydrobromide (4 [5 :.t 49 I62-amino-I-henzyl-5-(2-chlorophenyl) I I I I) I Z'imidaZoIIne (35 i 66)hydrohromide l7 Z-amino-4-(4-fluorophenyI)-2- l I l I imidazolinehydrobromide (*8 i (:0) 27 Z-am ino-4-( 3-chlorophenyl )-2- SA SA SA 3SA imidazoline hydrobromide (i 5(1) 33Zumino-4-I4-(trifluoromethyl)phenylI SA SA SA 3 SA 2-imidazoline I (297i 52) hydrobromide 54 2 amin o-4-(3-methoxyphenyl)-2- SA I SA 2 SAimidazoline hydrobromide (178 i I2I) 55 2-amino-4-l 3-( benzyloxy phenyl]-2- A A A 6 A imidazoline hydrobromide (39] ;t 58) 56 2-am ino-4-[3,4-dimethoxyphenyl ]-2- SA A A 5 A imidazoline hydrobromide (394 i 69)57 2-amino-4-(3-hydroxyphenyl)-2- SA A A 5 A imidazoline hydrobromide(505 t 96) 58 2-amino4-(3,4 dihydroxyphenyH-2- A SA VA 6 A imidazolinehydrobromide (6]9: 96)

Inactive I Preparation infra.

Compounds of the present invention particularly preferred for theirpotent antihypertensive effects are:

2-amino-4-(4-chlorophenyl)-2-imidazoline and its hydrobromide,

its hydrobromide, 2-amino-4-[3,4-dimethoxyphenyl]-2-imidazoline and itshydrobromide, 4-(4-chlorophenyl)-2-(methylamino)-2-imidazoline and itshemimucate, 2- (4-chlorobenzylamino)-4- phenyl-Z-imidazoline and itsfumarate.

The known art imidazoline, 2-amino-4-phenyl-2- imidazoline at a 5mg./kg. body weight subcutaneous dose has no demonstrable activity inthe DOCA hypertensive rat model and is considered to be essentiallyinactive.

The antihypertensive and neuronal blocking therapeutic process of thepresent invention is carried out in mammals by systemic administrationof a non-toxic effective dose of the imidazolines of the presentinvention ranging from about 0.01 to 50 milligram per kilogram of bodyweight of the mammal. By systemic administration it is intended toinclude both oral and parenteral routes. Examples of parenteraladministration are intramuscular, intravenous, intraperitoneal andsubcutaneous administration. The dosage will vary with the form ofadministration and particular compound chosen. Generally, the compoundis administered at a dosage substantially less than the dose of thecompound which is thought to be effective. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. As a general rule, it will be found that whenthe composition TABLE u -camratar ANTlHYPhR'lENSlVE ACTIVITY RA'l INGActivity Based On Area Under Actual B.P. /1 Decrease 71 DecreaseComposite Example" Chemical Name Decrease in B.P. Time Curve TotalRating 59 2henzylamino-4-phenyl-2- SA SA A 4 AI imidazoline fumarate(325 3: 82) 60 2(4-chlnrobenzylamino)-4-phenyl- A A VA 7 A Z-imidazolinefumarate (612 i 71) 6l 2-(3-dimethylaminopropylamino)-4- SA SA SA 3 SAphenyl-Z-imidazoline dihydrochloride (268 i l 19) 62 2-(2,6-dichlorobenzylidenehydrazino) A A v A 6 A4-(2-chlorophenylJ-Z-imidazoline (450 i 66) hydriodide 634-(4-chlorophenyl)-2-(methy|amino) VA A 7 A 2imidazoline (522 i 107)hemimucate 64 4-(4-chlorophenyl)-2-hydrazino-2- A SA A 5 A imidazolinehydrochloride (336 i 68) Numerical Rating Abbreviation Value Very VA 3Active Active A 2 Slightly SA 1 Active is administered orally, largerquantities of the imidazos I line will be required to produce the sameeffect as the smaller quantity given parenterally. In general. thecompounds of this invention are most desirably administered at aconcentration level that will afford effective results without causingany harmful or deleterious side effects.

The compounds which constitute this invention and their methods ofpreparation will appear more fully from a consideration of the followingexamples which. are given for the purpose of illustration only and arenot to be construed as limiting the invention in spiritor in scope.

EXAMPLE 1 2-Amino4-(2-chlorophenyl)-2-imidazoline bromide.

An aqueous solution of l-(2'chlorophenyl)ethylenediamine dihydrochloride(8.8 g., 0.04 mole) is made basic with 50 percent sodium hydroxide andthe free base isolated by extracting the basified solution withchloroform, drying the chloroform extract over potassium carbonate andconcentrating under reduced pressure. The free base thus obtained istaken up in ml. of benzene and treated with a solution of cyanogenbromide (4.2 g., 0.04 mole) in 50 ml. of benzene. After stirring for 4hrs. at room temperature, the mixture is filtered and the filtencakewashed with benzene to provide 9.1 g., (92 percent yield) of2-amino-4-(2-chlorophenyl)-2-imidazoline hydrobromide having a meltingpoint of 200C. Crystallization of this material from absoluteethanol-isopropyl ether affords 7.0 g. of analytically pure product,m.p. 2l3.52l5.5C. (corr.).

Analysis. Calcd. for C H CIN HBr (percent): C, 39.08; H, 4.01; N, l5.l9.Found (percent): C, 38.92; H, 4.08; N, 15.07.

hydroanol and reconcentrated untila solid is obtained. Trimthe aboveprocedure and crystallization of the imidazoline thus obtained fromabsolute ethanol-isopropyl ether provides analytically pured-2-amino-4-(2- chlorophenyl)-2-imidazoline hydrobromide, m .p. 162-l63C. (corr.); ['x],', '=-i- 94.4" (C= 1, H O).

Analysis. Calcd. for CgHwClNg'HBI' (percent):.C, 39.08; H, 4.01; N,l5.l9.'Found (percent): C, 38.80; H, 4.08; N, 14.93.

EXAMPLE 2 2-Benzylamino-4-(2-chlorophenyl)-2 imidazoline hydriodide.

A mixture of 2-methylthio-4-(2-ehlorophenyl)-2- imidazoline hydriodide(7.1 g., 0.02 mole) and benzylamine (2.14 g., 0.02 mole) in .75 ml. ofisopropanol is refluxed for 44 hr. At this'point, an additionalequivalent of benzylamine is added, reflux continued for an- 1 other 6hrs. and the mixture thenconcentrated under reduced pressure. Theresidual oil shaken w'ithl :-1 mixture of water-ether solidifies on.standin-g,-and is-collected, triturated with ether and dried toprovide5.3 g. of product having a melting point of 1.30 1 35C. Crystallizationof this material from .absolute ethanolisopropyl ether affordsanalytically v pure 2- benzylamino-4-( 2-chlor0phenyl )-2- imidazolinehydriodide, m.p. l47149C. ('corr.).

Analysis. Calcd. for C H ClN -Hl' (percent): C,

46.45; H, 4.14; N, 10.15. Foundv (percent): C, 46.18;

EXAMPLE 3 4-(2-Chlorophenyl)-2-hydrazino-2-imidazoline hydriodide. I

Hydrazine hydrate (85%, 39 g., 0.05 mole) is added in one portion to2-methylthio-4-(2-chlorophenyl)-2- imidazoline hydriodide 17.7g.,0.05.mole) in 200 ml. of absolute ethanol. The mixture is refluxedfor a 6 hr. period and then concentrated in vacuo to provide a residualoil which is successively taken up in absolute'ethration of the solidwith absolute ethanol provides 13.2 g. (78% yield) of material having amelting point of -182C., crystallization from isopropyl alcoholisopropylether provides analytically pure 4-(2 chlorophenyl)-2-hydrazino-2-imidazo1ine hydriodide.

Analysis. Calcd. for C H ClN 'Hl (percent): C, 31.92; H, 3.57; N, 16.55.Found (percent): C, 31.93; H, 3.58; N, 1.6.74.

EXAMPLE 4 4-(2-Chlorophenyl)-2-hydroxyamino 2-imidazoline hydrochlorideTo 2-methylthio-4-( 2-chlorophenyl )-2-imidazoline hydriodide (7.09 g.,0.02 mole) in 25 ml. of methanol is added a solution of methanolicsodium methoxide prepared-by the addition of sodium (0.46 g., 0.02 mole)to 25 ml. of methanol. The mixture is concentrated under reducedpressure and the residue taken up in anhydrous ether, filtered, andthe'filtrate concentrated in vacuo. The resulting oily residuesolidifies on.

scratching and is triturated with ether. to provide 4.1 g.

of I 2 methylthi'o-4-(2 chlorophenyl)-2-imidazoline, m.p. 7880 C.

Reaction of 2-methy'lthio-4-(2-chlorophenyl)-2- imidazoline (.4 g.,0.018mole) with hydroxylamine hydrochloride (1.39 g.,.0.02 mole) in 50ml. of absolute ethanol according to the procedure of Example 2 provides4-(2 chlorophenyl)-2-hydroxyamino-2- imidazoline hydrochloride. Ananalytical sample obtained by crystallization from acetonitrile-methanolhas a melting point of l75.5l77.5C. (corr.).

Analysis. Calcd. for C -H ClN O'HCl (percent): C,

43.56; H, 4.47; N, 16.94. Found (percent): C, 43.50;

EXAMPLE 5 4-(2-Chlorophenyl)-2-isopropylidene hydrazino-Z-imidazoline'hydriodide.

To a hot solution of 4-(2-chlorophenyl)-2-hydrazino- Z-imidazolinehydriodide (3.38 g., 0.01 mole) in 30 ml.

of water is added 1 ml. of acetone and two drops of acetic acid. Themixture is refluxed for 0.5 hr., cooled, and filtered to provide 2.9 g.of analytically pure 4-(2- chlorophenyl)-2-isopropylidene hydrazino-2-imidazoline hydriodide, m.p. 205.5207-5C. (corr.).

Analysis. Caled. for C,' H,;,ClN.,'Hl (percent-)9 C, 38.06; H, 4.26; N,14.80. Found (percent): C, 38.15; H, 4.43; N, 14.96.

' EXAMPLES 6-16 Other representative examples of the compounds of thepresent invention prepared according to the procedure described inExample 1 from the indicated phenylethylenediamine reactants areenumerated in the following table.

' TABLE III.-Il\/IIDAZOLINES ,N-H. R

Calvd. Found Example No. Phenylethylenediamine reactant R B M.P., 0.Formula C II N C II N 6 1-(4-chlorophenyl)-ethylenedian1ine 4-Cl H241-242 C llmClN fiBr 30.08 4.01 15.10 38.87 4.22 15.02 71-(4-br0mophenyl)-ethylenedia nine 4-Br H 239-2405 CaHmBrN l-lBr 33.673.45 13. 09 33. 76 3.46 13.20 l-(2, 4-dichlorophenyl)-ethylenedia-4-0101 H 1035-2005 CH0C12N1.HBr 34.75 3.24 13.51 35.00 3.03 13. 50

1111110. 9... 1-(2, 6diehlorophenyl)-ethylenedia- 2,6 diCl H 233-235CqI'I0ClzN3.HBl 34.75 3.24 13.51 34.97 3.17 13.61

mine. 10 l-(3, 4-diehlorophenyl)-ethylenedia- 3,4-diCl H 213-215CnH9Cl2N3.HB1 34.75 3.24 13.51 35.02 3.22 13.27

mine. 11 1-glfimethylphenyl)-ethylenedia- S-CH: H 148449 CmH NMHBr 46.895.51 16.40 47.04 5.56 16.33 no. 12 1-(4-rnethylphenyD-ethylenedia- 4-OH3H 185-187.5 C111H11N1.HBr 46.80 5.51 16.40 46.63 5.31 16.14

mine. 13 1-(4-methoxyph0nyl)-ethylenedia- 1-01110 H 210.5-211 C10H1N3O.HBr 44.13 5.18 15.44 44.35 5.32 15.32

T111118. 14 1-(4-benzyloxyphenyD-ethylenediar 40111.0 H 2105-2245C1eH17N1O.HBr 55.13 5. 21 12.07 55. 22- 5.10 11. as

mine. l-(biphenyl)ethylenedlamine 4-C3H5 H 256-258 C13l-I11N1.HBr 56.615.07 13.20 56.31 5.04 13.20 16 fl-Benzylamlno-2-ehlorophenethyl- 2-010.11.011. 2215-2235 0.811110110311131 52.40 4.07 11. 40 52.07 4.05 11.40

- am no. g

' 'FX KMPIKT ISF 7 TABLE IVJ-ADDITI'ONAIJ IMIDAZOLINES-C0niinued Furtherexemplification of the imidazolines of the R B A X present invention islisted below in Table IV. The imid- 3 H NH B 1 azolmes are prepared bycyclization of the appropri- 25 4 ately substitutedphenylethylenediamine with cyanogen bromide according to the proceduredescribed in Ex- 44;... 11 MIN", I ample l. or by displacement of methylmercaptan from m 4-substituted-2-methylthio-2- midazolme according to w45" Cm H mu m the procedures described in Examples 24. The 1 mphenylethylenediamines and the 4-substituted-2-meth- 4 1:: 21,1111]c'iffIIII 1 it Nl'l: Hr ylthio-2-imidazolines intermediates are obtainedutilizg 5": 1}} ing substituted benzaldehydes according to methods51.-.. 2.1,5-01 0111.. ll NllNlIn I 52--.- 2.4.3111 C1117... H II; Brdescrlbed fully below 53.... 3011140411101 11 N11, or

7' TAeiii iV-Kb oi'rto'iiXiI 11711512511353 Eramplo No. 17: Ml.190.0200.5 C. (corr.). (311106. for C HmFNa. HBr (percent); C, 41.55; H,4.26; N, 16.15. Found (percent): 0, 41.62; H.4. 16. 8 5

Example No. 27'. lVLP. 168.5l70.5 C. (corr.). Calcd. for C H ClN1. HBr(percent): 0, 39.08, H, 4.01; N. 15.19. Found (percent): 0, 39.36; H,3.98; N, 15 0 0 Example No. 33: Mi. 135.513I.5 C. (corr.). Calcd. forCmH F1N1. I'IBI' (percent): 0, 33.72; H, 3.58; N, 13.55. Found(percent): C, 33.91; 11, 3.66; N, 13.66.

21. Example No. 17: mp l99.0-200.5C. (corr.). Calcd. for C H FN 'HBr(percent): C, 4l.55; H, 4.26; N, 16.15. Found (percent): C, 41.62; H,4.28; N, 16.08.

b. Example No. 27: mp. l68.5l70.5C. (corr.). Calcd. for C H ClN 'HBr(percent): C, 39.08; H, 4.01; N, 15.19. Found (percent): C, 39.36; H,3.93; N, 15.02.

c. Example No. 33: mp. l35.5137.5C. (corr.).

Calcd. for C H F N tHBr (percent): C, 38.72; H, 3.58; N, 13.55. Found(percent): C, 38.91; H. 3.66; N, 13.66.

EXAMPLE 54 EXAMPLE '5 2-Amino-4-[3 benzyloxy)phenyl]-2-imidazolinehydrobromide 1 Cyclization of 1-(3-ben2yloxyphenyl)- ethylenediamine iscarried out according to the procedure of Example 1. The analyticallypure product (from ethyl acetate) has a melting point of l78.5180.5C.(corr.).

Analysis. Calcd. for c gHflNg'HBr (percent): C, 55.18; H, 5.21; N,12.07. Found (percent): C, 55.45; H, 5.12; N, 12.06.

EXAMPLE 56 2-Amino-4-[ 3 ,4-dimethoxyphenyl ]-2-imidazoline hydrobromideI Cyclization of 1-( 3 ,4-dimethoxyphenyl ethylenediamine is carriedoutaccording to the procedure of Example 1. The analytically pure product(from acetone isopropyl ether) has amelting point of158.5159.5C.(corr.). 3 Analysis. Calcd. for C H N-yHBr (percent): C,43.72; H, 5.34; N, 13.90. Found (percent): C, 43.73; H, 5.26; N, 13.91;

EXAMPLE 57 2-Amino4-( 3-hydroxyphenyl )-2-imidazoline hydrobromide2-Amino-4-[ 3-( benzyloxy)phenyl ]-2-imidazoline hydrobromide isdebenzylated in a Parr apparatus employing 10 percent palladium oncarbon catalyst in ethanol. The analytically pure product (fromacetonitrile) has a melting point of l 19.'5122.5C. (corr.).

Analysis. Calcd. for CgHnNgO'HBI' (percent): C, 41.87; H, 4.69; N,16.28. Found (percent): C, 41.62; H, 4.76; N. 15.99.

EXAMPLE 5 s EXAMPLE 59 2-Benzylamino4-phenyl-2-imidazoline-fumarate.

A mixture of 2-methylthio-4-phenyl-2-imidazoline hydriodide (8.0 g.,0.025 mole) and benzylamine 2.68 g., 0.025 mole) in 100 ml.ofisopropanol is refluxed for two days and the mixture concentrated. Theresidual oil is stirred with 200 ml. of hot water, water insolublematerial separated, and the aqueous solution-made basic with sodiumhydroxide, extracted with chloroform, and the chloroform extract driedover potassium carbonate. Concentration of the dried chloroform extractprovides'an oil which is taken up in absolute ethanol and acidified withfumaric acid. Addition of isopropyl ether to the acidifiedsol'ut'ionprovides the imidazois line product 4.5 g., mp. 203205C.Crystallization from methanol-ethanol provides analytically purebenzylamino-4-phenyl-2-imidazoline fumarate. mp.

203-.204C. (corr.).

Analysis. Calcd. for C H N /z C H O (percent): C, 69.88; H, 6.19; N,13.58. Found percent): C, 70.03;

EXAMPLE 2-(4-Chlorobenzylamino)-4-phenyl-2-imidazoline fumarate.

Reaction of 2-methy1thio-4-phenyl-2-imida2oline hydriodide with4-chlorobenzylamine is carried out according to the procedure of Example59. The analytically pure product (from acetone) has a melting point of1.80.5 182.5C. (dec.) (corr.).

Analysis. Calcd. for C H ClN /2C H O, (percent): C, 62.88; H, 5.28; N,12.22. Found (percent): C, 63.08; H, 5.50; N, 12.22.

2-(3-Dimethylaminopropylamino)-4-phenyl-2- imidazoline dihydrochlorideReaction of 2-methylthio-4-phenyl-2-imidazoline hydriodide withdimethylaminopropylamine in absolute ethanol iscarried out according tothe procedure of Example 59- The analytically pure product (fromisopropyl'etherabsolute ethanol) has a melting point of 208- 210C.(corr.).

Analysis. Calcd. for C H N '2HCl (percent): C, 52.66; H, 7.58; N, 17.55.Found (percent): C, 52.60; H, 7.58; N, 17.36.

EXAMPLE 62 2-(2,6aDichlorobcnzylidenehydrazino )-4-( 2-chlorophenyl)2-imidazoline hydriodide.

An equimolar' mixture of 4-(2-chlorophenyl)-2- hydrazine-Z-imidazolinehydriodide and 2,6 dichlorobenzaldehyde in 50 ml. of absolute ethanolwith a catalytic amount of acetic acid is refluxed for 18 hr. and thenconcentrated under reduced pressure. Trituration of the residue thusobtained with ethanol provides the imidazoline product which iscrystallized from acetonitrile-isopropyl ether to analytical purity,m.p. 209.5210.5C. (corr.).

Analysis. Calcd. forC H Cl N -Hl (percent): C, 38.77; H, 2.85; N, 11.30.Found (percent): C, 38.50; H, 2.79; N, 11.46. I

EXAMPLE 63 4(4 Chlorophenyl)-2-(methylamino)-2-imidaZoline hemimucate.

A mixture of 2-methylthio-4-(4-chlorophenyl)-2- imidazoline (5.65 g.,0.025 mole) and methylamine hydrochloride (1.75 g., 0.025 mole) in 100ml. of isopropanol is refluxed for 15 hr. and then concentrated underreduced pressure. The residual oil is taken up in water, converted tothe free base with sodium hydroxide and extracted with chloroform. Afterdrying the chloroform extract over potassium carbonate, the chloroformsolvent is removed and the residue taken up in refluxing methanol. Mucicacid (2.6 g.) is added to the hot solution and the mixture filtered.Concentration of the filtrate and trituration of residue with hotacetone provides a solid which is crystallized from methanol- 19 Iis'opropyl ether to provide analytically pure product, m.p.179.5-180.5C. (dec) (corr.).

Analysis. Calcd. for CmH 2ClN3' /2 C HmOg (percent): C, 49.60; H, 5.44;N, 13.35. Found (percent): C, 49.35; H, 5.53; N, 13.26.

EXAMPLE 64 4-(4-Chlorophenyl)-2 hydrazino-2-imidazoline hydrochloride.

2-Methylthio-4-(4}chlorophenyl)-2-imidazoline hydriodide (8.9g, 0.025mole) and 2 g. of 85% hydrazine hydrate in 75 ml. of isopropyl alocholis refluxed for about 6 hr. and then concentrated under reducedpressure. Trituration of the residue with ethyl acetate provides4-(4-ch1oropheny1)-2-hydrazino-2-imidazoline hydriodide, m.p. 125127C.The imidazoline hydriodide is passed through an ion exchange column toconvert it to the hydrochloridesalt. The hydrochloride salt crystallizedfrom ethyl acetate-methanol provides analytically pure 4-(4-chlorophenyl )-2-hydrazino-2- imidazoline hydrochloride, m.p.155.5157.5C. corr.

Analysis. Calcd. for CH ClN HCl (percent): C, 43.74; H, 4.90; N, 22.67.Found (percent): C, 43.51; H, 5.09; N, 22.56.

EXAMPLE 65 4(4-Chlorophenyl)-2-(benzylamino)-2-imidazoline hydriodide.

Reaction of 2-methylthio-4-(4-chlorophenyl)-2- imidazoline hydriodideand benzylamine according to the procedure of Example 59 and preparationof the hydriodide-salt according to Example 63 affords 4-(4-chlorophenyl)-2-(benzylamino)-2-imidazoline hydriodide, m.p. l18.5-120.5C. (corr.) (from isopropanolisopropyl ether). 3

Analysis. Calcd. for C H ClN 'H1 (percent). C, 46.45; H, 4.14; N, 10.16.Found (percent): C, 46.23; H, 4.23; N, 10.08.

EXAMPLE 66 4-(4-Chlorophenyl)-2-(4-chlorobenzylamino-2- imidazolinehydriodide.

Reaction of 2-methylthio-4-(4-chlorophenyl)-2- imidazoline hydriodideand 4-chlorobenzylamine according to the method of Example 59 providesthe imidazoline,4-(4-chlorophenyl)-2-(4-chlorobenzylamino)-2-imidazoline hemi mu catemp. 126-128- C. (from acetonitrile). Neutralizing the imidazolinehemimucate with base and acidifying the base in an inert solvent with H1provides:

4-(4-chlorophenyl)-2-(4-chlorobenzylamino-2- imidazoline hydriodide,m.p. 152154C. (from acetonitrile-isopropyl ether).

EXAMPLE 674-(3,4-Dichlorophenyl)-2-(3,4-dich1orobenzylamino)-2-imidazolinehydriodide.

Reaction of 2-methylthio-4-(3,4-dichlorophenyl)-2- imidazolinehydriodide and 3,4-dichlorobenzy1amine according to the method ofExample 59 provides the imidazoline product, m.p. 171-l73C. (corr.)(from ethyl acetate).

Analysis. Calcd. for CwHmClqNg'H] (percent): C, 37-

.16; H, 2.73; N, 8.13. Found (percent): C, 36.94; H,

EXAMPLE 68 4-( 3 ,4-Dichlorophcnyl )-2-( 4-chlorobenZyl-umino-Z-imidazoline hydriodide.

Reaction of 2-methylthio-4-(3,4-dichlorophenyl)-2- imidazolinehydriodide and 4-chlorobenzylamine according to the method of Example 59provides the imidazoline, zylamino)-2-imidazoline. The hydriodide saltis prepared from the imidazoline base by'acidifying with H1 in an inertsolvent and has a melting point of 1 l61 19- C. (corr.) (fromisopropanol-isopropyl ether).

Analysis. Calcd. for C,,,H Cl;,N ,'Hl (percent): C, 39.82; H, 3.13; N,8.71. Found (percent): C, 39.87; H, 3.14; N, 8.64.

EXAMPLE 69 4-(3,4-Dichlorophenyl)-2-(allylamino)-2- imidazoline.

Reaction of 2-methylthio-4-(3,4-dichlorophenyl)-2- imidazoline andallylamine hydrochloride according to the procedure of Example 59provides the imidazoline, 4-(3,4-dichlorophenyl)-2-(allylamino)-2-imidazoline. Various salts'can beprepared by dissolving or suspending the imidazoline base in an inertsolvent and acidifying with an appropriate acid. There can be mentionedby way of example salts such its:-

4-(3,4-dichlorophenyl)-2-(allylamino)-2-imidazoline hydrochloride,4-(3,4-dichlorophenyl)-2-(allylamino)-2-imidazoline fumarate,4-(3,4-dichlorophenyl)-2-allylamino)-2-imidazoline hydriodide, and4-(3,4-dichlorophenyl)-2-allylamino-Z-imidazoline hemimucate.

EXAMPLE 70 EXAMPLE 71 4-(3,4-Dichlorophenyl)-2-(benzyl)-2-imidazolinehydriodide.

Reaction of 2-methylthio-4-(3,4-dichlorophenyl)-2-' imidazolinehydriodide and benzylamine according to the method of Example 59provides the imidazoline, 4- (3,4-dichlorophenyl )-2-( benzylamino)-2-imidazoline hydriodide, m.p. 151.5153C. (corr.) (from ethylacetate).

4-(3,4-dichlorophenyl)-2(4-chloroben- 2'1. Analysis. Calcd. for CmHClriNqf-HI.(percentk: C,.

42.88; H, 3.60; N, 9.38. Found (percent-)1 C,43.05; H,"

EXAMP' IJE 72; 4-( 4-Ch1oropheny1)-2- (3,4 dichloroben2ylamin0)-25.-imidazoline hydriodide. I 1

Reaction of 2-methy1th'io-4-(4-ch10rophenyl):2: imidazoline hydriodideand 3,4-dichlorobenzylamine according to the method of Example 59provides the.

imidazoline, 4-.( 4-chlorophenyl )-2-( 3,4-dich10roben:

zy1amirio)-2-imida-zoline. Thehydriodide. saltqis; prepared from theimidazoline baseby. acidifying; with-H1 in inert solvent and'has ameltingpoint of l.52. -l54C. (corr.) (from ethyl acetate).

Analysis. Calcd. for C H Cl N 'Hl (percent): C, 39-

.82; H, 3.13; N, 8.71. Found. (percent): C, 39.61; H,

STARTING MATERIALS foregoing examples and intermediates required fortheir preparation are-obtained by methods described as. follows.

PREPARATION A. OF a-AMlNO- PHENYLACETONITRILES 1.a-(Benzylamino)-2-ch1oropheny1acetonitrilehy-.

drochloride. l

cation of the ethereal extract witheth'anolic. hydrogen:- chlorideprovides 269 g. of. a-(benzylaminohZ chlorophenyl-acetonitri1e.having-a.- melting point of.

l49l56C. Crystallization from acetone-isopropyl ether provides materialwith a melting point of.

Analysis. Calcd.: C, 61.44; H 4.81; N,- 9.56. Found:

C, 62.21; H, 4.92; N, 9.68. 9.56.

Following the procedure describe d above for .ar(.be'n=,

zylamino)-2-chlorophenylacetonitrile hydrochloride.

. The various phenylethylenediamines employed in the .wit'nethanolichydrogen chloride provides a-amino-4- but employing equimolar amountsof-thefollowing,

benzaldehydes: 2,4-dichlorobenzaldehyde, f

3-methy1benzaldehyde, 4-methylbenzaldehyde, 4-methoxybenza1dehyde,4-biphenylcarboxaldehyde,. 3-chlorobenzaldehyde,3-trifluoromethylbenzaldehyde, 4-trifluoromethylbenzaldehyde, in placeof 2-chlorobenza1de1iyde, thereis produced:

2. a-(benzylamino)-2,4#dichlorophenylacetonitrile hydrochloride, mlp.138 144 6.; 3. a-(benzylamino) 3:methylphenylacetonitrile hydrochloride,m.p. l66-'170.C.;-

4. a-( benzylamino )-4-methylphenylacetonitrile. hyv

drochloride, m:p. 1299-1329C. W 5. a-(benzylamino)-4-methox-yphenylacetonitrile hydrochloride; 6.a-(benzylamino)-4-biphenylacetonitrile hydrochloride, m.p. ll'52C.;'".1. I

7. a-(benzylamino)-3chlorophenylacetonitrile hydrochloride, m.p.172-l78C.;

8. ==aatbenzylamino)-3 tritluoromethylphenylacetonitril'e hydrochloride;

awtbenzylamino)-4-trifluoromethylphenylacetonitrile-hydrochloride.

10. a-Amino-4-chloroph'enylacetonitrile hydrochloride. 1 .A. mixtureofl4-chlorobenzaldehyde (80 g., 0.57

-mole) and sodium bisulfite (59.2 g., 0.57 mole) in 300 m1. ofwateris'stirred for 1.5 hr. at room temperature and thenheatedto 60C.for 0.5 hr. Ammonium hydroxide (1 5N138 ml'.,.'0.57 mole) is rapidlyaddcd to the .mixtureand stirring continued for 0.5 hr. at 60C. After.coolitigthe; mixtureto below 10C., a solution of sodium cyanid'e.(2.8g,0.57 mole) in ml. of water is added ove-ra. l 0 minute period andstirring continued for.an-addit1onal 2.5 hr; at room temperature.Extraction of-themixture with chloroform, drying thechloroform-extract-overpotassium carbonate and concentratingundrreducedpressureprovides a residual oil. The oil is taken up in 5.0 ml. ofabsolute ethanol and acidified withethanolic'hydroge'nchloride. Onaddition of traction oflthisxmixture-.wi-th,;ether; dryingthe. etherealextratover potassium carbonate. and then acidifyingbromophenylacetonit'rile I"182C.

l2.;a Amino-4 benzy1oxyphenylacetonitrile.

A solution of 4=henzyloxybenzaldehyde (41.5 g;, 0.195 mole) 'in1400' m1.of 'acetonitrileflis added in one portionzatoa solution of sodiumcyanide. (9.6 g.) and ammonium chloride (11.7 g..)-in- 400 ml. of water.The mixture is stirred overnight, filtered and .the filter-cakewashedwit h-waterto provide 1111 g. of la-amino-4benzyloxyphenylacetonitrile free. base, m.p. l08l 12C.

a-Arnin04;benzyloxyphenylac'etonitrilehydrochloride prepared "fromthefree base is purified by crystallization from. absolute et-hanolisopropyl ether, m.p. l 78."-179 C..

Analysis. Calcd.: C, 65.57; H, 5.50;- N, 10.20. Found: C, 651.37; H.521;N, 9.96..

1.3 a-Amino?2,6adichlorophenylacetonitrile hydrochloride; v

In ,the manner. given above for-( l 2)a-amino-4-benzyloxyphenylacetonitrile but employing methanol in place of5 acetonitrile, 2,6=dichlorobenzaldehyde, ammonium-"chloride; and sodiumcyanide'were reacted to give: a-amino-2,6,dichlorophenylacetonitrilehydrow chloride, .m.'p. 1.92.-'-200C.

hydrochloride. mp.

14;: a'-Amino3,4-dich1orophenylacetonitrilehydrobromophenylacetonitrile, 3,4-dichlorobenzaldehyde, ammoniumchloride and sodium cyanide were reacted to givea-amino-3,4-dichlorophenylacetonitrile hydrochloride, m.p. 184185C.

l a-( Benzylamino)-4-fluorophenylacetonitrile hydrochloride. a In themanner given above for l) a-(benzylamino)- 2-ehlorophenylacetonitrilehydrochloride, 4- tluorobenzaldehyde substituted for 2chlorobenzaldehyde provides a- (benzylamino)-4- fiuorophenylaeetonitrilehydrochloride, m.p. 127-130C. 16. a-(Benzylamino)-4-trifluoromethylphenylacetonitrile hydrochloride.

In the manner given above for (l) a-(benzylamino)-2-ehlorophenylacetonitrile hydrochloride, 4-trifluorornethylbenzaldehydeprovides a-(benzylamino)-4-trifluoromethylphenylacetonitrilehydrochloride, m.p. l5215 8C.

l7. a-(Benzylamino)-3-methoxyphenylacetonitrile hydrochloride.

In the manner given above for (1) a-(benzylamin o)-2-chlorophenylacetonitrile hydrochloride, 3- methoxybenzylaldehydeprovides a-(benzylamino)-3- methoxyphenylacetonitrile hydrochloride,mzp.

155-158C. 18. a-Amino-3-benzyloxyphenylacetonitrile hydrochloride.

In the manner given above for (11) a-amino-4- bromophenylacetonitrilehydrochloride, 3-benzyloxybenzaldehyde providesa-amino-3-benzyloxyphenylacetonitrile hydrochloride, m.p. l50160C.

19. a-Amino-3,4-dimethoxyphenylacetonitrile hydrochloride.

In the manner given above for (l0) a-amino-4- chlorophenylacetonitrilehydrochloride, 3,4-dimethoxybenzaldehyde providesa-amino-3,4-dimethoxyphenylacetonitrile hydrochloride, m.p.- 173-1'75C.Crystallization from isopropyl ether-absolute ethanol affordsanalytically pure material, m.p. 173-l75C. (corr.).

Analysis. Calcd. (percent): C, 52.52; H, 5.73; N, 12.25. Found(percent): C, 52.81; H, 5.60; N, 12.19.

period of 0.5 hr. under a nitrogen atmosphere. After;

stirring for 0.5 hr., the mixture is firstv hydrolyzed-by the carefuladdition of 100 ml. of water and then coneen-.. trated under reducedpressure to provide an oil. This residual oil is taken up in ethanolandacidified with ethanolic hydrogen chloride (36 ml., 5.6N, 0.2 mole).Evaporation of the acidified solution underreduced 24 provides thefreeamine-which is isolated by extracting thebasifi'ed mixture withchloroform, drying the chlo roform extract over potassium carbonate, andconcentrating in vacuo. The residual oil thus obtained is taken up inethanolic hydrogen chloride (27 ml., 5.6N, 0.15 mole) and diluted withan equalvolume of isopropyl ether to provide 19.0 g., (68%) of1-(2,6-dichlorophenyl)ethylenediamine dihydrochloride, m.p. 329-33lC. g

Following the procedure describedabove for 1-(2,6-dichlorophenyl)ethylenediamine dihydrochloride but employing equimolaramounts of the following a-amin'ophenylacetonitriles:

a-amino- 4-chlorophenylacetonitrile, a-amino-4-bromophenylacetonitrile,a-amino-4-benzyloxyphenylaeetonitrile,a-(benzylamino)-3-trifluoromethylphenylacetonitrile, 1a-(benzylamino)-4-trifluo'romethylphenylacetonitrile,

in place of a-amino-2,6-dichlorophenylacetonitrilc,

there is produced:

2. 1-(4-chlorophenyl)ethylenediamine dihydrochloride, m.p. 285-288C.; 3.1-(4-bromophenyl)ethylenediamine dihydrochloride, m.p. '300'305C.; I 4.1-(4-benzyloxyphenyl)ethylenediamine dihydrochloride, m'.p. 246253C.; 5.a-(benzylamino)-3-trifluoromethylphenethylamine dihydrochloride,.

a-( benzylamino )-4-trifluoromethylphenethylw mine dihydrochloride. 7.B-(Benzylamino)-2-chlorophenethylamine dihydrochloride.a-(Benzylamino)-2-chlorophenylaeetonitrile hydrochloride is converted tothe free base by treatment with 10% sodium hydroxide. A solutionol'a-benzylamino-Z- chlorophenylracetonitrile (64.2 g, 0.25 mole) in 500ml. of anhydrous ether is added to a stirred suspension of lithiumaluminum hydride (38 g., 1 mole) in 1 liter of anhydrous ether under anitrogen atmosphere over g a 0.5 .hr. period at 0C. After the additionis complete,

pressure and treatment with 10% sodium hydroxide vides the mixture isstirred at 0C. for 5 hr. and then at room temperature overnight.Hydrolysis of the reaction mixture is carried out by the sequentialaddition of water (38 ml.), 15% sodium hydroxide (38 ml.) and a ml.portion of water. Filtrationof the mixture removes inorganic materialand addition of 5N ethanolic hydrogen chloride ml, 0.65 mole) to thefiltrate pro- 82 'g., (97%) of B-(benzylamino)-2- chlorophenethylaminedihydrochloride, m.p. 2l621- 9C.

Followingthe procedure described above forB-benzylamino-Z-chlorophenethylamine dihydrochloride but employingequimolar amounts of the following 2- (benzylamino )phenylacetonitriles:

a-(benzylamino)-2,4-dichlorophenylaeetonitrile,

a-(benzylarnino)-3-methylphenylacetonitrile, a-(benzylamino)4-methylphenylacetonitrile, a-(benzylamino)-4-methoxyphenylacetonitrile,a-(benzylamino)-4-biphenylacetonitrile,a-(benzylamino)-3-chlorophenylacetonitri1e,a-amino-3,4-dichlorophenylacetonitrile,

in place of oz-(benzylamino)-2- chlorophenylacetonitrile, there isproduced:

8 B-(benzylamino)-2,4-diehlorophenethylamine di- 9.,8-(benzylamino)-3-methylphenethylamine dihydrochloride, m.p. l75-l80C.;

10. B-( benzylamino)-4-methylphenethylamine dihydrochloride, m.p. 3 l2315C.;

I l. B-(benzylamino)-4-methoxyphenethylamine dihydrochloride;

12. B-( benzylamino)-4-biphenylethylamine dihydrochloride, m.p.257-259C.;

l3. /3-(benzylamino)-3-chlorophenethylamine dihydrochloride, m.p.225-230C.;

l4. B-amino-3,4-dichlorophenethylamine dihydrochloride, m.p. 283285C.

15. l-( 2-Chlorophenyl )ethylenediamine dihydrochloride. A suspension of,B-( benzylamino)-2- chlorophenethylamine dihydrochloride (33.4 g., 0.1mole) in 200 ml. of methanol is debenzylated by hydrogenating over 10%palladium on carbon catalyst at 50 p.s.i. or atmospheric pressure in ahydrogenation apparatus. Before charging the hydrogenation vessel withthe catalyst, the catalyst is first treated in a beaker with smallportions of methanol. The methanol solvent is allowed to ignite and theflame is immediatelysmothered with a watch glass. When the catalyst nolonger ignites freshly added methanol, it is washed into thehydrogenation vessel and the reduction carried out. After one molarequivalent of hydrogen is taken up, the catalyst is collected and thefiltrate evaporated under reduced pressure. Crystallization of theresidue thus obtained from methanol-isopropyl ether providesanalytically pure l-( 2-chlorophenyl )ethylenediamine dihydrochloride,m.p. 299-30lC.

Analysis. Calcd: C. 39.45; H, 5.38; N. l 1.50. Found: C. 39.52; H, 5.47;N. 11.58.

Two equivalents of d-camphorsulfonic acid is added to one equivalent ofdl-(2-chloropl'ienyl ethylenediamine in ethanol. Successivecrystallizations from ethanol affords optically purel-l-(2-chlorophenyl)ethylenediamine di-d-camphorsulfonate salt, m.p.244-248C.; [c21 6.5 (c 1, H O).

The d-camphorsulfonate mother liquors which are enriched with thed-diamine are concentrated under reduced pressure and the residueconverted to free diamine with sodium hydroxide and then to the tartaricacid salt. Successive crystallizations for ethanol-water affordsoptically pure d-l-( 2-chlorophenyl)ethylenediamine l-tartrate salt,m.p. 206209C.; [011 --5.0 (c l, H O).

Following the procedure described above for l-(2-chlorophenyl)ethylenediamine dihydrochloride but employing equimolaramounts of the following B-benzylaminophenethylamine dihydrochlorides:

B-( benzylamino )-2,4-dichlorophenethylamine dihydrochloride,

B-( benzylamino )-3-methylphenethylamine dihydrochloride, I

,8-(benzylamino)-4-methylphenethylamine dihydrochloride,

,8-( benzylamino)-4-methoxyphenethylamine drochloride,

B-( benzylamino)-4-biphenylethylamine dihydrochloride,

B-( benzylamino )-3-chlorophenethylamine dihydrochloride.

,B-( benzylamino )-3-trifluoromethylphenethylamine dihydrochloride,

B-( benzylamino )-4-trifluoromethylphenethylamine dihy- 26dihydrochloride, in place of B-(benzylamino)-2-chlorophenethylaminedihydrochloride, there is produced:

16. l-( 2,4-dichlorophenyl )ethylenediamine dihydrochloride, m.p. 305-310C.;

17. l-( 3-methylphenyl )ethylenediamine dihydrochloride, m.p. 238243C.;

18. l-( 4-methylphenyl )ethylenediamine dihydrochloride, m.p. 3l2-3l5C.;

l9. l-(4-methoxyphenyl)ethylenediamine dihydrochloride, m.p. 264-266C.;

20. l-(4-biphenyl)ethylenediamine dihydrochloride,

m.p. 325327C.;

2 l. l-( 3-chlorophenyl )ethylenediamine dihydrochloride, m.p.275-278C.;

22. l-(3-trifluoromethylphenyl)ethylenediamine dihydrochloride;

23. l-(4-trifluoromethylphenyl)ethylenediamine dihydrochloride.

24. l-( 4-Fluorophenyl )ethylenediamine dihydrochloride, m.p. 255265C.Prepared by debenzylation of ,B-(benzylamino)-4-fluorophenethylaminedihydrochloride, m.p. 229232C., obtained by lithium aluminum hydridereduction of a-( benzylamino)-4-fluorophenylacetonitrile.

25. l-(4-Trifluoromethylphenyl)ethylenediamine dihydrochloride, m.p.25926lC. Prepared by debenzylation of/3-(benzylamino)-4-trifluoromethylphenethylamine, m.p. 242.5245C.obtained by reduction of B-(benzylamino)-4- trifluorophenylacetonitrilewith diisobutyl aluminum hydride.

26. l-( 3-Methoxyphenyl )ethylenediamine dihydrochloride, m.p. 245-250C.Prepared by debenzylation of B-(benzylamino)-3-methoxyphenethylaminedihydrochloride obtained by reduction ofa-(benzylamino)-3-methoxyphenylacetonitrile with lithium aluminumhydride.

27. l-(3?Benzyloxypheny|)ethylenediamine dihydrochloride m.p. 225235C.prepared by reduction of a-am ino-3-benzyloxyphenylacetonitrile withlithium aluminum hydride.

28. l-( 3.4-Dimethoxyphenyl )ethylenediamine dihydrochloride, m.p.25826lC. Prepared by catalytic reduction ofa-amino-3,4-dimethoxyphenylacetonitrile hydrochloride employing platinumoxide in ethanol with a molar equivalent of hydrogen chloride.

29. l-(3,4 Dibenzyloxyphenyl)ethylenediamine dihydrochloride, m.p.24l243C. Prepared by lithium aluminum hydride reduction of a-amino-3,4-dibenzyloxyphenylacetonitrile.

30. l-( 3-Chlorophenyl )ethylenediamine dihydrochloride, m.p. 255270C.Prepared by lithium aluminum hydride reduction of a-amino-3-chlorophenylacetamide.

C. PREPARATION OF 4-SUBSTlTUTED-2-METH- YLTHIO-Z-IMIDAZOLINES.

l 2-Methylthio-4-( 2-chlorophenyl)-2-imidazoline hydriodide.

An aqueous solution of l-(2-chlorophenyl)ethylenediamine dihydrochloride(51 g., 0.197 mole) is converted to the free base by treating with 50%sodium hydroxide. Isolation of the free base is carried out in the usualmanner by extracting the basified solution with chloroform, drying thechloroform extract over potassium carbonate, and concentrating the driedsolution under reduced pressure. Residual free base in taken up in 400ml. of 80% ethanol and 12 ml. (15 g., 0.197 mole) of carbon disulfide isadded in one portion. After stirring and refluxing the mixture for 1hr., 1.5 ml. of concentrated hydrochloric acid is added and the mixturestirred for 10 hr. at reflux and then at room temperature for anadditional 10 hr. period. The mixture filtered, washed with water, anddried provides 1 1.0 g. (73%) of 4-(2chlorophenyl)-2-thio-2-imidazoline, m.p. 2 l2l2C.

A solution of 4-(2-chlorophenyl)-2-thio-2- imidazoline (l 1.0 g., 0.052mole) and'3.6 ml. (8.] g., 0.057 mole) of methyl iodide in 75 ml. ofisopropanol is refluxed for 3 hr. and the mixture concentrated in vacuoto approximately one-half volume. Dilution of the concentrated mixturewith 1 liter of isopropyl ether provides l7.3 g., 94%) of product havinga m.p. of l55-l60C. Crystallization from absolute ethanolisopropyl etherprovides analytically pure 2-methylthio-4-(2-chlorophenyl)-2-imidazoline hydriodide, m.p. l64-l67.9C.

Analysis. Calcd.: C, 33.86; H, 3.41; N, 7.90. Found: C, 33.74; H, 3.40;N, 7.63

Following the procedure described above for 2-methylthio-4-(2-chlorophenyl)-2-imidazoline but employing equimolaramounts of the following 1- phenylethylenediamines:

l-( 4-chlorophenyl )ethylenediamine,

l-(2,4-5-trimethylphenyl)ethylenediamine,

B-benzylamino-4-chlorophenethylamine,

B-methylamino-4-chlorophenethylamine,

l-( 4-n-butoxyphenyl )ethylenediamine,

(4-biphenylyl)ethylenediamine,

l-( 4-isopropylphenyl )ethylenediamine,

l-( 4'-chlorobiphenylyl )ethylenediamine,

l-( 2,4,6-trichlorophenyl )ethylenediamine,

l 3-methyl-4,o-dichlorophenyl )ethylenediamine,

l-phenylethylenediamine, in place of l-(2-chlorophenyl)ethylenediaminethere is produced:

2. 2-methylthio-4-(4-chlorophenyl)-2-imidazoline hydriodide,

3. 2-methylthio-4-(2;4,6-trimethylphenyl)-2- imidazoline hydriodide,

4. 2-methylthio-3-benzyl-4-(4-chlorophenyl)-2- imidazoline hydriodide,

5. 2-methylthio-3-methyl-4-(4-chlorophenyl)-2- imidazoline hydriodide,

6. 2-methylthio-4-(4-n-butoxyphenyl)-2 imidazoline hydriodide,

7. 2-methylthio-4-(4-biphenylyl)-2-imidazoline hydriodide,

8. 2-methylthio-4-(4-isopropylphenyl)-2-imidazoline hydriodide,

. 2-methylthio-4-(4'-chloro-4-biphenylyl)-2- imidazoline hydriodide,

l0. 2-methylthio-4-( 2,4,6-trichlorophenyl )-2- imidazoline hydriodide,

l l. 2-methylthio-4-( 3-methyl-4,6-dichlorophenyl )-2- imidazolinehydriodide,

l2. 2-methylthio-4-phcnyl-2-imidazoline hydriodide,

While several specific embodiments are disclosed in the foregoingspecification, it. will be appreciated by those skilled in the art thatother modifications may be made without departing from the spirit andscope of the appended claims. a

What is claimed is:

l. A compound selected from the group consisting of imidazolines havingformula wherein when Y is said phenyl,

A is selected from the group consisting of benzylamino, halobenzylamino,3-

I dimethylaminopropylamino; wherein when Y is said R-phenyl radical,

' 'R is halogen, lower alkyl, benzyloxy, lower alkoxy,

lower dialkoxy, 3-hydroxy, 3,4-dihydroxy, trifluoromethyl, phenyl.4-halophenyl, or 4-(lower alkyl phenyl with the proviso that when R isselected from the group consisting of halogen and lower alkylthe phenylring can have up to two additional substituents independently selectedfrom the group consisting of halogen and lower alkyl; and

A is amino, hydroxyamino, lower alkylamino, benzylamino,halobenzylamino, dihalobenzylamino, allylamino, cycloalkylamino.hydrazino, halobenzylidenehydrazino, dihalobenzylidenehydrazino, oralkylidenehydrazino from two to six carbon atoms inclusive.

2. The compound of the group defined in claim 1 which is2-amino-4-(2-chlorophenyl)-2-imidazoline.

3. The compound of the group defined in claim 1 which is 2-amino-4-(2-chlorophenyl )-2-imidazoline hydrobromide.

4. The compound of the group defined in claim 1 which is4-(2-chlorophenyl)-2-hydrazino-2- imidazoline.

SI The compound of the group defined in claim 1 which is 4-(2-chlorophenyl )-2-hydrazino-2-imidazoline hydriodide.

6. The compound of the group defined in claim 1 which is4-(2-chlorophenyl)-2-isopropylidenehydrazino-2-imidazoline.

7. The compound of the group defined in claim 1 which is4-(2-chlorophenyl)-2-isopropylidenehydrazino-2-imidazoline hydriodide.

- 8. The compound of the group defined inclaim l which is2-amino-4-(4-chlorophenyl)-2-imidazoline.

9. The compound of the group defined in claim 1 which is2-amino-4-(4-chlorophenyl)-2-imidazoline hydrobromide.

l0. The compound of the group defined in claim 1 which is2-amino-4-(4-bromophenyl)-2-imidazoline.

ii. The compound of the group defined in claim I which is2-amino-4-(4-bromophenyll-2-imidazoline hydrobromide.

12. The compound of the group defined in claim I which is 2-amino-4-(2,4-dichlorophenyl )-2- 29 imidazoline.

13. The compound of the group defined in claim 1 which is imidazolinehydrobromide. 2

14. The compound of the group defined in claim 1 which is2-amino-4-(2,6-dichlorophenyl)-2- imidazoline.

15. The compound of the group defined in claim 1 which is2-amino-4-(2,6-dichlorophenyl)-2- imidazoline hydrobromide.

1 6. The compound of the group defined in claim 1. which is2-amino-4-(p-tolyl)-2-imidazoline.

17. The compound-of. the group defined in claim 1 which is2-amino-4-(p-tolyl)-2-imidazoline hydrobromide.

18. The compound of the group defined in claim 1 which is2-amino-4-(4-biphenylyl)-2-imidazoline.

19. The compound of the group defined in claim 1 which is.2-amino-4-(4-biphenylyl)-2-imidazoline ,hydrobromide. I

20. The compound of the group defined in claim 1 which v is imidazoline.4

21. The compound of the group defined. in claim 1' which is2-amino.-4-(3,4-di chlorophenyl)-2- 2-amino-4-(2,4 dichlorophenyl)-2- 30imidazoline hydrobromide.

22. The compound of the group defined in claim I which imidazolinehemimucate.

, 2-amino-4-(3,4-dichlorophenyl)-2- 24.-The compound of the groupdefined in claim 1 which is 2-amino-4-[3,4-dimethoxyphenyl]-2-imidazoline.

25, The compound of the group defined in claim 1 which is2-amino-4-[3,4-dimethoxyphenyl]2- imidazoli'ne hydrobromide.

26. The compound of the group defined in claim 1 which is 2-benzylamino-4-phenyl-2-imidazoline.

27. The compound of the group defined in claim I which is2-benzy1amino-4-phenyl-Z-imidazoline fumarate.

28. The compound of the groupdefined in claim 12-(4-chlorobenzylamino)-4-phenyl-2- imidazoline furnarate.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. I3,821,244 DATED 1 June 28, 1974 g v I INVENTOMS) 3 William Lesley-Matier and William Timmey Comer It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

. Title page, first column at entry identified as "[75]",

change "William Timmey" to read-William Timmey Comer.

Title page, first column at entry identified as "[63]", change "Jan." toread-August-.

Table II bridging columns 9, l0, and 11, 12, change the following:Example 16, delete "(35 r 66)" under column entitled "Actual B. P.Decrease" and insert under column "Area Under 2 Decrease Time Curve; IExample 27, change i 56)" to read-(l57 t 56);

Example 33, delete "(297 t 52)" under column entitled "Actual B. P.Decrease" and insert under column entitled "Area Under Z Decrease TimeCurve"; I

Example 62, delete "(450 i 66)" under column entitled "Actual B. P.Decrease" and insert under column entitled "Area Under Z Decrease TimeCurve".

Page 2 I V i v UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIONPATENT NO. X DATED 3 June 28, 1974 v lNvENToms) I William Lesley Matierand William Timmey Comer It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Example 63, delete "(522 i 107)" from column entitled "Actual B. P.Decrease" and insert under column entitled "Area Under Z Decrease TimeCurve".

Table III bridging columns 15 and 16, Example 14 under column "R",change 4-C H O" to read--4C H CH 0.

Column 20, line 60 change "(benzyl)" to read(benzylamino)--.

In the Claims:

Claim 1, line 2, after' "having" insert "the".

Claim 1, delete as part of formula pictured at lines 4-10.

Signed and Scaled tIi'lS o twenty-fifth D2) of N0vember1975 [SEAL]Arrest:

RUTH C. MASON C. MARSHALL DANN v films-ring Officer (imrn iyr'miicr ofParents and TrUl/L'IHUr/(S Li Q

2. The compound of the group defined in claim 1 which is2-amino-4-(2-chlorophenyl)-2-imidazoline.
 3. The compound of the groupdefined in claim 1 which is 2-amino-4-(2-chlorophenyl)-2-imidazolinehydrobromide.
 4. The compound of the group defined in claim 1 which is4-(2-chlorophenyl)-2-hydrazino-2-imidazoline.
 5. The compound of thegroup defined in claim 1 which is4-(2-chlorophenyl)-2-hydrazino-2-imidazoline hydriodide.
 6. The compoundof the group defined in claim 1 which is4-(2-chlorophenyl)-2-isopropylidenehydrazino-2-imidazoline.
 7. Thecompound of the group defined in claim 1 which is4-(2-chlorophenyl)-2-isopropylidenehydrazino-2-imidazoline hydriodide.8. The compound of the group defined in claim 1 which is2-amino-4-(4-chlorophenyl)-2-imidazoline.
 9. The compound of the groupdefined in claim 1 which is 2-amino-4-(4-chlorophenyl)-2-imidazolinehydrobromide.
 10. The compound of the group defined in claim 1 which is2-amino-4-(4-bromophenyl)-2-imidazoline.
 11. The compound of the groupdefined in claim 1 which is 2-amino-4-(4-bromophenyl)-2-imidazolinehydrobromide.
 12. The compound of the group defined in claim 1 which is2-amino-4-(2,4-dichlorophenyl)-2-imidazoline.
 13. The compound of thegroup defined in claim 1 which is2-amino-4-(2,4-dichlorophenyl)-2-imidazoline hydrobromide.
 14. Thecompound of the group defined in claim 1 which is2-amino-4-(2,6-dichlorophenyl)-2-imidazoline.
 15. The compound of thegroup defined in claim 1 which is2-amino-4-(2,6-dichlorophenyl)-2-imidazoline hydrobromide.
 16. Thecompound of the group defined in claim 1 which is2-amino-4-(p-tolyl)-2-imidazoline.
 17. The compound of the group definedin claim 1 which is 2-amino-4-(p-tolyl)-2-imidazoline hydrobromide. 18.The compound of the group defined in claim 1 which is2-amino-4-(4-biphenylyl)-2-imidazoline.
 19. The compound of the groupdefined in claim 1 which is 2-amino-4-(4-biphenylyl)-2-imidazolinehydrobromide.
 20. The compound of the group defined in claim 1 which is2-amino-4-(3,4-dichlorophenyl)-2-imidazoline.
 21. The compound of thegroup defined in claim 1 which is2-amino-4-(3,4-dichlorophenyl)-2-imidazoline hydrobromide.
 22. Thecompound of the group defined in claim 1 which is4-(4-chlorophenyl)-2-(methylamino)-2-imidazoline.
 23. The compound ofthe group defined in claim 1 which is4-(4-chlorophenyl)-2-(methylamino)-2-imidazoline hemimucate.
 24. Thecompound of the group defined in claim 1 which is2-amino-4-(3,4-dimethoxyphenyl)-2-imidazoline.
 25. The compound of thegroup defined in claim 1 which is2-amino-4-(3,4-dimethoxyphenyl)-2-imidazoline hydrobromide.
 26. Thecompound of the group defined in claim 1 which is2-benzylamino-4-phenyl-2-imidazoline.
 27. The compound of the groupdefined in claim 1 which is 2-benzylamino-4-phenyl-2-imidazolinefumarate.
 28. The compound of the group defined in claim 1 which is2-(4-chlorobenzylamino)-4-phenyl-2-imidazoline.
 29. The compound of thegroup defined in claim 1 which is2-(4-chlorobenzylamino)-4-phenyl-2-imidazoline fumarate.